Nanoparticles: synthesis and applications

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Nanoparticles: synthesis and applications

7

Nguyen Hoang Nam1,2 and Nguyen Hoang Luong2 1

Faculty of Physics, Hanoi University of Science, Vietnam National University, Hanoi, Hanoi, Vietnam 2Nano and Energy Center, Hanoi University of Science, Vietnam National University, Hanoi, Hanoi, Vietnam

7.1 INTRODUCTION Nanoparticles are defined by the worldwide federation of national standards bodies, the International Organization for Standardization (ISO), as nanoobjects with all external dimensions in the nanoscale, where the lengths of the longest and shortest axes of nanoobjects do not differ significantly (ISO/TS 80004-2:2015). Though nanoscale is basically ranged from 1 to 100 nm, nanoparticles can be categorized by three size ranges: larger than 500 nm, between 100 and 500 nm, and between 1 and 100 nm (European Commission, 2010). With respect to the size and the size distribution, nanoparticles may exhibit size-related intensive properties. If they are small enough to confine their electrons, they produce quantum effects and exhibit unexpected properties, for example, gold nanoparticles appear red in solution (see, for instance, Eustis and El-Sayed, 2006), and melt at much lower temperatures than that in slab form (Buffat and Borel, 1976). The high surface-area-to-volume ratio of nanoparticles provides the significant changes in properties related to contact/surface area, such as catalytic (Astruc, 2008), surface-enhanced plasmon resonance (Melaine et al., 2015), etc. Depending on the composition and structure, nanoparticles can be of single properties such as metallic, dielectric, semiconductor, magnetic, or multifunctional which include more than one feature from single-property nanoparticles. Their applications, or potential applications, are in many different fields (Salata, 2004; Mody et al., 2010; Lu et al., 2007; Zhang et al., 2008; Nguyen et al., 2015; and references therein). Among those, the advantages of nanoparticles in applications in life sciences and the environment are due to the fact that their size is comparable with the dimensions of objects such as viruses (about 10
100 nm) or cells (about 1
10 μm). This gives nanoparticles an ability to attach to biological entities without changing their functions, while the high surface-area-to-volume ratio of

Materials for Biomedical Engineering: Inorganic Micro and Nanostructures. DOI: https://doi.org/10.1016/B978-0-08-102814-8.00008-1 © 2019 Elsevier Inc. All rights reserved.

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nanoparticles permits strong bonds with surfactant molecules. In environmental applications, the specific features (small size, large surface area) of nanoparticles can provide a tool for very sensitive detection of a specific contaminant from the presence of which pollution often arises. The engineering of nanoparticles can also offer opportunities to treat environmental contamination. In this chapter we focus on the synthesis, functionalization, and applications of metallic, semiconductor, magnetic, and multifunctional nanoparticles. Compiling all the literature would greatly exceed the scope of this work, instead, we present typical and representative examples for discussion on the synthesis, functionalization, and applications of those nanoparticles.

7.2 SYNTHESIS OF NANOPARTICLES 7.2.1 CHEMICAL REDUCTION Chemical reduction is an effective wet-chemical method for making zero-valent nanoparticles based on chemical-reducing aqueous salts of metals, such as silver nitrate (AgNO3) in the case of synthesis of silver nanoparticles, for instance. To reduce the precursor metal salt, at least one reducing agent is used to produce electrons for metal ions that reduce them to become zero-valent. Commonly used reductants are borohydride, citrate, and ascorbate. Reduced nanoparticles are stabilized by a stabilizing agent. An example of a stabilizing agent is cetyltrimethylammonium bromide [(C16H33)N(CH3)3Br; CTAB], which is widely used in gold nanoparticle synthesis. The stabilizing agents can be reducing agents themselves, such as citrate of sodium in making silver nanoparticles (Shenava Aashritha, 2013). For more details the reader is referred to the review paper by Alaqad and Saleh (2016) and references therein.

7.2.2 COPRECIPITATION Precipitation is the carrying down by a precipitate of soluble substances under certain conditions (Patnaik, 2004). Generally, when the concentration of substances reaches supersaturation, a nucleation suddenly appears in solution. The nucleation will be grown by the diffusion on to its surface which then becomes nanoparticles. During the growth, the nucleation needs to be slowed down in order to get uniform nanoparticles. Several methods can be listed as precipitation: coprecipitation, microemulsion/inverse microemulsion, polyol, etc. Coprecipitation is a convenient way to synthesize Fe3O4 nanoparticles (Lu et al., 2007; Quy et al., 2013; Dung et al., 2016; Khalil, 2015; Mascolo et al., 2013). The mixture of two chloride salts of FeCl2 and FeCl3 with 1:2 molar ratios of Fe21/Fe31 was vigorously stirred and kept at 70 C before NH4OH was added resulting in the black color precipitation. The Fe3O4 nanoparticles were collected after purifying through magnetic separation with ethanol and distilled water

7.2 Synthesis of Nanoparticles

several times to decontaminate the residual chemicals. By modifying the pH and ion concentration in solution, the size of nanoparticles can be controlled.

7.2.3 SEEDING The seeding method was discovered by Frens (1972, 1973), where nanoparticles are grown by the reduction of salt in aqueous solution which contains seed nanoparticles. In this method, the stabilizers are used to control the size and shape of growing nanoparticles. This method was developed over the years using various types of seeding, reductant agents, and stabilizers (Xu et al., 2007; Han et al., 2009; Perrault and Chan, 2009; Ziegler and Eychmuller, 2011; Rioux and Meunier, 2015). For example, the method which was developed by Perrault and Chan in 2009, reduces HAuCl4 in gold nanoparticles seed-contained aqueous solution using hydroquinone. The gold nanoparticle seed can act in conjunction with hydroquinone to catalyze the reduction of gold ions into their surface. If the stabilizer is citrate, typically the seed nanoparticles were prepared by the citrate method. Using this method, the size of nanoparticles can be grown at least 30
300 nm.

7.2.4 MICROEMULSION AND INVERSE MICROEMULSION Microemulsion is a popular method to synthesize nanoparticles, where microemulsions are an isotropic and thermodynamically stable mixture of “oil,” water, and surfactant, or in combination with a cosurfactant. The basic types of microemulsions are direct (oil dispersed in water) and reverse (water dispersed in oil). The small drops of aqueous phase (micelles) may contain salts and/or other ingredients, and the “oil” may actually be the mixture of the surfactants. The reaction to form nanoparticles also can be realized when the micelles mix with each other and the growth of the nanoparticles is controlled by the surfactants in “oil” (Lopez-Quintela and Rivas, 1993). Using this method, the Fe3O4 nanoparticles can be synthesized (Feltin and Pileni, 1997) and also can be functionalized with a silica layer. This method can also be used to prepare Fe3O4/Au core
shell nanoparticles to prevent the oxidation of magnetic nanoparticles (MNPs) as well as form the biocompatibility (Boutonnet et al., 1982). Furthermore, the inverse microemulsion method is the simplest way to produce multifunctional nanoparticles by creating the silica matrix in aqueous phase, which will fix the single particles inside (Dung et al., 2016).

7.2.5 HYDROTHERMAL METHOD In the hydrothermal method, the crystals of nanoparticles are grown by heterogenous reaction under conditions of high temperature and high pressure from substances which are insoluble at normal temperature and pressure (Byrappa and Adschiri, 2007). The crystal growth is carried out in an apparatus consisting of a

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steel pressure vessel called an autoclave, in which nutrients are supplied along with water. Hydrothermal synthesis is usually carried out below 300 C. The critical condition gives a favorable reaction field for formation of nanoparticles, owing to the enhancement of the reaction rate and large supersaturation based on the nucleation theory. This method has been used to synthesize metal oxide nanoparticles in supercritical water (Hayashi and Hakuta, 2010), metal nanoparticles (Kim et al., 2014), and semiconductor nanoparticles (Bui et al., 2014; Hoa et al., 2011; Williams et al., 2007).

7.2.6 SONOELECTRODEPOSITION Sonoelectrodeposition is a useful synthesis method for nanoparticles and has been successfully applied to prepare metallic nanoparticles such as FePt and CoPt (Luong et al., 2011; Nam et al., 2012; and references therein). Sonoelectrodeposition is a technique combining the advantages of electrodeposition and mechanical waves of ultrasound to produce metallic nanoparticles (Zhu et al., 2000). In Section 7.4 we discuss silver nanoparticles. One of main disadvantages of the conventional synthesis methods for silver nanoparticles, including chemical reduction, is the presence of unexpected toxic ions in the final products. The toxic ions in the product are mostly the ions of the silver precursor, such as nitrate and thiolsulfate. A good silver precursor such as silver acetate can be used (Irzh et al., 2007), however, this chemical is expensive and manipulation is difficult under ambient conditions. Tuan et al. (2011) reported a modified sonoelectrodeposition technique to obtain silver nanoparticles in a nontoxic solution. The modification is that a silver plate was used as the cathode instead of silver salts thus allowing the avoidance of unexpected ions from the salts.

7.3 FUNCTIONALIZATION/COATING OF NANOPARTICLES 7.3.1 FUNCTIONALIZATION OF NANOPARTICLES Functionalization of nanoparticles can be defined as the addition of a chemical functional group on their surface in order to achieve surface modification that enables their self-organization and renders them compatible (Subbiah et al., 2010). The most widely used functional groups are amino, biotin, steptavidin, carboxyl, and thiol groups (Bruce and Sen, 2005). The main purpose of functionalizing nanoparticles is to cover their surface with a molecule that possesses the appropriate functionality needed for the designed application. For many biomedicine applications, nanoparticles need to be functionalized in order to conjugate with biological entities such as DNA, antibodies, and enzymes. For more details on the functionalization of nanoparticles, its methods, and class, as well as its implications in biomedical sciences, the reader may be referred to, for instance, the review by Subbiah et al. (2010).

7.3 Functionalization/Coating of Nanoparticles

We focus here on the functionalization of gold nanoparticles and MNPs discussed in Section 7.4. For application in detecting breast cancer cells, gold nanoparticles synthesized by a chemical reduction were functionalized with 4-aminothiolphenol (4-ATP, sometimes called p-aminothiolphenol [PATP]). For basal cell carcinoma (BCC) detection, different amounts of 4-ATP solutions were added to gold nanoparticles coated by CTAB. CTAB on the surface of gold nanoparticles was replaced by 4-ATP to form gold nanoparticles functionalized with 4-ATP (Au-4ATP). Fe3O4 nanoparticles were functionalized using 3-aminopropyl triethoxysilane (APTS). APTS is a bifunctional molecule, an anchor group by which the molecule can attach to free
OH surface groups. The head group functionality
NH2 is for conjugating with biological objects. The amino-NP is ready to conjugate with the DNA of the herpes virus and with the antiCD4 antibody.

7.3.2 SILICA COATING OF MAGNETIC NANOPARTICLES Maintaining the stability of MNPs for a long time without agglomeration or precipitation is an important issue (see, for instance, Lu et al., 2007). The protection of MNPs against oxidation by oxygen, or erosion by acid or base, is necessary. The common method is protection by a layer which is impenetrable, so that oxygen, for example, cannot reach the surface of the particles. It is noted that the stabilization and protection of particles are often closely linked with each other. One of the ways to protect MNPs is coating them with silica. A silica shell not only protects the magnetic cores, but can also prevent direct contact of the magnetic core with additional agents linked to the silica surface that can cause unwanted interactions. The coating thickness can be controlled by varying the concentration of ammonium and the ratio of tetraethylorthosilicate (TEOS) to H2O. The surfaces of silica-coated MNPs are hydrophilic, and are readily modified with other functional groups (Ulman, 1996). Quy et al. (2013) and Hieu et al. (2017) have prepared Fe3O4/SiO2 nanoparticles by coating MNPs with silica using TEOS.

7.3.3 MULTIFUNCTIONAL NANOPARTICLES Recently, multifunctional nanoparticles have gained wide attention due to their advantages in the goal of applications. Potentially, multifunctional nanoparticles which include individual physicochemical properties of nanoparticles, such as plasmonic metallic nanoparticles, photoluminesable semiconductor nanoparticles or quantum dots, and MNPs, can complement some of the limitations of conventional applications using single nanoparticles, particularly in biomedicine. For example, bifunctional nanoparticles which are composed of MNPs and metallic nanoparticles not only can be used as optical labels in bioimaging, diagnosis and therapy, but also allow some biomolecules to be tagged and separated, together with targeted drug delivery and magnetic resonance imaging under the induction of an external magnetic field (Cai et al., 2014; Sotiriou et al., 2011; Ilovitsh et al., 2015; Giani et al., 2012; Sun et al., 2006). Multinanoparticles can be in

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core
shell structures or in the complex structures which are a combination of at least two types of single nanoparticles. Core
shell structured nanoparticles can be classified into inorganic/inorganic, inorganic/organic, organic/inorganic, organic/organic, core/multishell, and movable core/hollow shell nanoparticles (Chaudhuri and Paria, 2012). The synthesis approaches to nanoparticles can be divided into top-down and bottomup methods. The top-down approaches often use externally controlled tools to cut, mill, and shape materials into the designed nanoscale structures, for example, lithography methods, laser beams, mechanical techniques. The bottom-up approaches exploit the chemical properties of the molecules to cause them to self-assemble to become nanoparticles, such as chemical synthesis discussed above. The bottom-up methods can produce much smaller nanoparticles and are cost-effective, compared to the top-down methods. Both methods are used in the synthesis of core
shell structured nanoparticles. However, since ultimate control is needed for achieving a uniform coating of the shell, the bottom-up approach has proven more suitable. A combination of the two methods can also be utilized, for example, core particles synthesized by the top-down method but then coated by the bottom-up approach in order to maintain precise shell thickness. In general, various methods were used to prepare core
shell nanoparticles. For example, to produce iron oxide@Ag core
shell nanoparticles, several methods were used including impregnation (Liu et al., 2012), surface functionalization followed by deposition (Liu et al., 2010), solvo-thermal reduction (Liu and Li, 2009), and chemical reduction (Hu et al., 2010; Sun et al., 2012). Reducing agents such as glucose and sodium borohydride are used for the reduction of silver salts, and the surface functionalization of iron oxide nanoparticles by different surface-modifying agents is required. Hu et al. (2010) used glucose for the reduction of Ag(NH3)21 to Ag, which is adsorbed onto the surface of silicacoated iron oxide which is prepared by the coprecipitation method. Liu et al. (2010) have reported the surface functionalization of Fe3O4 surface by APTS followed by reduction of AgNO3 using sodium citrate and sodium borohydride. Sun et al. (2012) have used sodium borohydride as the reducing agent for the reduction of Ag(NH3)21 to obtain Fe3O4@Ag core
shell nanoparticles. Dung et al. (2016) used ultrasound to assist in the reduction of silver ions following this strategy. Liu and Li (2009) have used dimethylformamide as the reducing agent during solvo-thermal synthesis of γ-Fe2O3@Ag microspheres. In parallel, one-step synthesis using thermal decomposition of silver acetate in the presence of iron oxide microspheres is also applicable and does not require the addition of any external reducing agent or surface modification of iron oxide (Sharma and Jeevanandam, 2013). To control the overall size and the shell thickness, a microemulsion method, where water droplets act as a template or nanoreactor, is preferable to a bulk medium. Other types of multifunctional nanoparticles are the complex structures of materials, which is the combination of at least two types of single nanoparticles. Similar to a core
shell structure, the nanomaterials used in complex structures

7.3 Functionalization/Coating of Nanoparticles

can be categorized by two types of nanoparticles: organic, which includes micelles, liposomes, nanogels, dendrimes, and inorganic, which includes magnetic, semiconductor, lanthanide, and metallic nanoparticles. The combination can be achieved in many ways, however it is needed to fulfill the requirements of the applications. For example, the multifunctional nanoparticles should have superparamagnetic properties in order to be applied in drug delivery and DNA separation, and they should have plasmonic properties in order to be applied as biolabeling agents, and they should also be biocompatible. The simplest combination which fulfills these requirements is the complex of Fe3O4 nanoparticles with superparamagnetic properties and Ag nanoparticles with plasmonic properties in a matrix of SiO2 which provide the biocompatibility and also improve the stability of Ag and Fe3O4 nanoparticles. Surface activator polyvinylpyrrolidone (PVP) was used to control the size of silver nanoparticles, which were synthesized by a wet-chemical reduction method with NaBH4 as reductant. The synthesized nanoparticles were coated with 4-ATP to form functionalized Ag4ATP nanoparticles. These functionalized nanoparticles were combined with the above-prepared Fe3O4 nanoparticles by an inverse microemulsion method to form multifunctional nanoparticles (Dung et al., 2014). In this method, the microemulsion was created by mixing the hydrophilic phase of the mixture of Ag-4ATP and Fe3O4 solution and the hydrophobic phase of toluene. The mixture of Ag-4ATP/Fe3O4 with different mass rates was moderated under a sonic bath for 2 hours, then TEOS was added to react with water in solution as in reaction (7.1). The formed SiO2 coating layer in amorphous conformation covers both initial particles. SiðOC2 H5 Þ4 1 2H2 O-SiO2 1 4C2 H5 OH

(7.1)

The multifunctional composites were also successfully prepared in a complex form using an ultrasound-assisted chemical method (Dung et al., 2017a). MNPs were firstly prepared by the coprecipitation method, then coated by a silica layer. The silica layer, after that, was modified by APTS. Silver ions were then absorbed on the surface of APTS-functionalized silica-coated MNPs. Under the ultrasonic wave of 200 W acting for 60 minutes these silver ions were reduced by sodium borohydride. In XRD characterization after synthesis, the relative intensity of diffraction peaks of silver crystals increases when the atomic ratio of silver to iron increases from 0.208 to 0.455. In parallel, all nanoparticles showed superparamagnetic properties with the saturation magnetization decreased from 44.68 to 34.74 emu/g with increasing silver:ion atomic ratio. The coexistence of strong surface plasmon absorption at 420 nm and these superparamagnetic properties make these particles promising for biomedical applications. In another way, MNPs can be directly functionalized with an amino group without coating by silica layer (Dung et al., 2017b). In this way, Fe3O4-ZnO multifunctional nanoparticles were successfully synthesized in aqueous solution by ultrasound-assisted thermolysis. The as-prepared Fe3O4 MNPs were modified by APTS to have free amine (2NH2) groups on their surface. Zn21 ions then were

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added and stirred to adsorb onto the surface of Fe3O4-NH2 nanoparticles in alkaline solution at pH 11. The solution was decomposed through thermolysis in an ultrasound bath. The characterization shows that photoluminescence of Fe3O4ZnO multifunctional nanoparticles was enhanced in visible light at a wavelength of 565 nm to allow detection, labeling, diagnosis, and therapy in biomedicine. Furthermore, they exhibit superparamagnetic properties of Fe3O4 with high saturation magnetization, which can be used for separation applications in biomedicine under an external magnetic field.

7.4 APPLICATIONS 7.4.1 APPLICATION OF GOLD NANOPARTICLES FOR BREAST CANCER CELL DETECTION Gold nanoparticles are promising candidates for cell imaging and tumor-targeted drug delivery (Sokolov et al., 2003; Paciotti et al., 2004; Jain, 2005), breast cancer diagnosis, and targeted therapy (Yezhelyev et al., 2006). Being a member of the epidermal growth factor receptor tyrosine kinase family, HER2 is found to be overexpressed in 20%
30% of human breast cancers (Harries and Smith, 2002; and references therein). Therefore, HER2 is an interesting target for breast cancer therapies. Anti-HER2 (trastuzumab, trade name Herceptin) is a humanized monoclonal antibody (mAb) designed specifically for antagonizing the HER2 function. Quynh et al. (2011) and Nguyen et al. (2015) have synthesized gold nanoparticles by a chemical reduction then applied them for imaging KPL4 breast cancer cells after conjugating them with trastuzumab. Fig. 7.1 shows the bright-field and dark-field microscopy images of breast cancer cells after being incubated with gold nanoparticles nonconjugated with trastuzumab as well as conjugated with trastuzumab (Nguyen et al., 2015). As can be seen from Fig. 7.1, when the gold nanoparticles were not conjugated with trastuzumab, the dark-field image showed no signal of the gold nanoparticles (A2). When the gold nanoparticles were directly conjugated with trastuzumab, the gold nanoparticles were bound onto cancer cells and these cancer cells were clearly observed in the dark-field image (A4) through the scattering light from the gold nanoparticles. When the 4-ATP functionalized gold nanoparticles (amino-gold nanoparticles) were covalently conjugated with trastuzumab through l-ethyl-3-(3dimethylaminopropyl) ethylcarbodiimide (EDC) connection, the gold nanoparticles also concentrated on the cancer cells, but these cancer cells were observed with slightly lower intensity in the dark-field image (A6) compared to those in image A4. Nguyen et al. (2015) pointed out, however, that the gold nanoparticles directly conjugated with trastuzumab could be stored in a freezer for only about 2 weeks before they lost their activity, while the gold nanoparticles covalently conjugated with trastuzumab were stable with storage for about two months.

7.4 Applications

FIGURE 7.1 Bright-field (A1, A3, A5) and dark-field (A2, A4, A6) microscopy images of breast cancer cells after being incubated with gold nanoparticles nonconjugated with trastuzumab (A1, A2), the gold nanoparticles conjugated with trastuzumab (A3, A4) and the amino-gold nanoparticles covalently conjugated with trastuzumab through EDC connection (A5, A6). After Nguyen, H.L., Nguyen, H.N., Nguyen, H.H., Luu, M.Q., Nguyen, M.H., 2015. Nanoparticles: synthesis and applications in life science and environmental technology. Adv. Nat. Sci.: Nanosci. Nanotechnol. 6, 015008.

7.4.2 BASAL CELL CARCINOMA FINGERPRINTED DETECTION Skin cancer is the most common cancer in humans and its incidence is increasing (Baxter et al., 2012). Worldwide, BCCs constitute about 74% of skin cancer cases (NCIN, 2013). Among the treatments for “high-risk” BCCs (i.e., BCCs on the

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face and neck, or recurrent BCCs), Mohs micrographic surgery (MMS) is the most efficient (Mohan and Chang, 2014). This procedure helps to maximize the removal of tumor cells, while spares as much healthy tissue as possible. However, the need for a pathologist or specialized surgeons to diagnose frozen sections during surgery has limited the wider use of MMS, which leads to cases of inappropriate inferior treatment. Frozen-section histopathology also requires arduous and time-consuming procedures, increasing the costs compared to standard methods of BCC excision. For skin cancer diagnosis, Raman spectroscopic imaging is a promising technique, because of its high sensitivity to molecular and structural changes associated with cancer. However, raster scanning Raman mapping requires long times for data acquisition, typically days for tissue specimens of 1 cm 3 1 cm. Recently, multimodal spectral imaging based on Raman spectroscopy and tissue autofluorescence was used to reduce the BCC diagnosis time to only 30
60 minutes, which becomes suitable for use during MMS (Kong et al., 2013; Takamori et al., 2015). An alternative method that could allow to reduce data acquisition and BCC diagnosis times during MMS is surface-enhanced Raman spectroscopy (SERS). It was discovered that strongly increased Raman scattering signals can be obtained in the very close vicinity of metal nanostructures, which are mainly due to resonances between optical fields and the collective oscillations of the free electrons in a metal. Thus SERS has attracted great interest in the biolabeling field because significant enhancement of the labeling signals of molecular vibrations on the metallic nanoparticles surface can be obtained. Quynh et al. (2016) studied surface-enhanced Raman (SER) signal of 4-ATP that was linked to the surface of gold nanoparticles conjugated with skin carcinoma cell antibody BerEP4. Gold nanoparticles with sizes ranged from 2 to 5 nm were prepared by a wet-chemical method using CTAB. The Au-4ATP-antibody solutions were dropped on the surface of the tissue sample and the SER scattering signals were collected and analyzed. Fig. 7.2 shows the fingerprinted landscape of SER signals of Au-4ATPantibody on a BCC tissue. Fig. 7.2A shows the colored image of a Gram-stained tissue, where the cancer cell area may be the dark-colored regions, for example, region A1, A2. However, the result of diagnosis essentially depends on the subjective decision of the pathologists because this nonspecific method may lead to misinterpretation of noncancer regions as cancer ones. Fig. 7.2B shows a brightfield microscopy image of the tissue, where B1 region corresponds to a hair follicle position, and B2 does not, although B1 and B2 have the same position on the tissue as regions A1 and A2 in Fig. 7.2A. Fig. 7.2C shows the result of an SER signal obtained by the principal component analysis (Quynh et al., 2016). Fig. 7.2D shows the result of the SER signal analyzed using only the intensity of SER peaks at 1075 cm21. The Au-antibody colloids are oriented close to the BCC surface by the antigen
antibody coupling. The carcinoma sections act as a dock where a high concentration of Au-4ATP-antibody particles is distributed, then the SER peak intensity at 1075 cm21 will be higher in these areas. In

7.4 Applications

FIGURE 7.2 Fingerprinted landscape of SER signals of Au-4ATP-antibody on BCC tissue. (A) Image of Gram-stained BCC tissue where A1 and A2 are the areas of suspected BCC; (B) bright-field microscopy image of tissue, where regions B1 and B2 are in the same position on the tissue as regions A1 and A2, respectively; (C) SER signal landscape obtained by principal component analysis, where regions C1 and C2 are in the same position on the tissue as regions A1 and A2, respectively; (D) the fingerprinted landscape of intensity of SER peaks at 1075 cm21, where regions D1 and D2 are in the same position on the tissue as regions A1 and A2, respectively. The difference between D1 and D2 shows that only red-colored D2 (and the similar-colored area) are the infected area, while D1 is not. After Quynh, L.M., Nam, N.H., Kong, K., Nhung, N.T., Notinger, I., Henini, M., et al., 2016. Surfaceenhanced Raman spectroscopy study of 4-ATP on gold nanoparticles for basal cell carcinoma fingerprint detection. J. Electron. Mater. 45, 2563
2568.

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Fig. 7.2C, the colored areas such as C1 and C2 can be considered as cancer regions. However, in Fig. 7.2D the area D1 does not show the high intensity of the peak at 1075 cm21, while the others, such as the D2 area, indicate very high intensity of the peak at 1075 cm21. From Fig. 7.2, only A2, B2, C2, and D2 regions can be definitely considered as the cancer areas, while A1, B1, C1, and D1 may assigned as the position of hair follicles where the cell concentration is higher than in other parts. Quynh et al. (2016) pointed out that, while the whole SER map collecting time should be longer than 2 hours (the collecting time of each spectrum was nearly 5 seconds), the fingerprinted image using peak height at 1075 cm21 can be observed in around 5 minutes. Hence, this method may represent a solution for quick diagnosis, even during operation.

7.4.3 ANTIBACTERIAL TEST USING SILVER NANOPARTICLES Silver nanoparticles (AgNPs) are commonly utilized nanomaterials due to their antibacterial properties, high electrical conductivity, and unique optical properties that can be used in various applications (Sondi and Salopek-Sondi, 2004). It is believed that the high affinity of Ag toward sulfur or phosphorus is the key element of its antibacterial property. As sulfur and phosphorus are found in abundance throughout cell membranes, AgNPs react with sulfur-containing proteins inside or outside the cell membrane, which in turn affects cell viability (Pal et al., 2007; Elechiguerra et al., 2005). Another theory proposed that Ag1 ions released from AgNPs can interact with phosphorus moieties in DNA, resulting in inactivation of DNA replication, or can react with sulfur-containing proteins to inhibit enzyme functions (Sharma et al., 2009). These properties allow the incorporation of AgNP into various matrices such as activated carbon (AC), polymer networks, textiles, and wound dressing materials (Sedaghat and Nasseri, 2011). Many approaches have been developed to obtain AgNP of various shapes and sizes, including chemical reduction, laser ablation, gamma irradiation, electron irradiation, chemical reduction by inorganic and organic reducing agents, photochemical method, microwave processing, thermal decomposition of Ag oxalate in water and in ethylene glycol, and sonoelectrochemical method (see references in Tuan et al., 2011). As pointed out in Section 7.2.6, one of main disadvantages of those methods is the presence of unexpected toxic ions in the final products. Tuan et al. (2011) report a modified sonoelectrochemical technique to obtain AgNP in a nontoxic solution. The silver particles are then directly loaded on AC produced by thermal activation of coconut husk. Here we concentrate to their work on the antibacterial properties of AgAC examined by inhibition growth of Escherichia coli. Fig. 7.3 shows the quantitatively antibacterial study of AgNP in LuriaBertani (LB) broth. It presents the dynamics of E. coli growth in only LB broth (negative control), TSC control [LB broth supplemented with 120 μL trisodium citrate (TSC) solution], and AgNP antibacterial tests (LB broth supplemented with AgNP of concentration from 2 to 200 μg/mL). In this figure, OD595 represents optical density at 595 nm (1 optical density at 595 nm, OD595, equals the

7.4 Applications

FIGURE 7.3 Bar chart of optical density at 595 nm, OD595, presenting Escherichia coli concentration in LB in the presence of different concentrations of AgNP (μg/mL) as a function of time (h). Each test was conducted after 4, 8, 24, and 30 h. It is clear that, with the concentration of AgNP $ 16 μg/mL, E. coli growth was inhibited. After Tuan, T.Q., Son, N.V., Dung, H.T.K., Luong, N.H., Thuy, B.T., Anh, N.T.V., et al., 2011. Preparation and properties of silver nanoparticles loaded in activated carbon for biological and environmental applications. J. Hazard. Mater. 192, 1321
1329.

concentration of 1.7 3 109 cells/mL). The initial number of E. coli inoculated into 2 mL LB medium of the tested tube was 1.7 3 106 cells, giving the final bacterial concentration of 8.5 3 105 cells/mL. It is observed that E. coli grew normally in the negative control and the TSC control. After 30 hours in the TSC control, the concentration of E. coli (OD595 5 2.5) is higher than that in the negative control (OD595 5 1.5) which suggests that TSC was not toxic to E. coli and may be even enabled for the growth of the bacteria. With the presence of AgNP, the situation is different because of the well-known antibacterial property of AgNP (Kim et al., 2007). When AgNP concentration was 2 μg/mL, the result is similar to that of the negative control because the low value of AgNP could not inhibit bacterial growth. With a higher AgNP concentration, the inhibitory effect appeared within 8 hours even at a low AgNP concentration of 4 μg/mL. Fig. 7.3 clearly shows that, with the concentration of AgNP . 16 μg/mL, the E. coli growth was inhibited.

7.4.4 MAGNETIC NANOPARTICLES MNPs are of great interest in biomedicine applications. In the applications described below these nanoparticles were synthesized by the coprecipitation method.

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7.4.4.1 Arsenic removal from water MNPs Fe3O4 were reported to adsorb arsenic ions from contaminated water (Leslie-Pelecky et al., 2005). In this environmental application, compared to other techniques currently used to remove arsenic from contaminated water, such as centrifuges and filtration systems, this method using MNPs has the advantage of being simple, and, most importantly, not requiring electricity. This is very important, because arsenic-contaminated sites are often found in remote areas with limited access to power (Filipponi and Sutherland, 2010). The arsenic adsorption abilities of Fe3O4, Fe12xCoxFe2O3 (Co-ferrites) and Fe12yNiyOFe2O3 (Ni-ferrites) with x 5 0, 0.05, 0.1, 0.2, 0.5 and y 5 0.2, 0.4 were studied with different conditions of stirring time, concentration of nanoparticles, and pH (Hai et al., 2008). The starting arsenic concentration of 0.1 mg/L was reduced about 10 times down to the maximum permissible concentration (MPC) of 0.01 mg/L after a few minutes of stirring. The removal process seemed not to depend considerably on the concentration of x in the Co-ferrites. Similar results were found for the Ni-ferrites, where the arsenic concentration was reduced to the MPC value after a stirring time of a few minutes and the removal did not change considerably with y. Studying also the effects of the weight of the nanoparticles on the removal process, Hai et al. (2008) showed that, after 3 minutes of stirring, the optimal weight to reduce arsenic concentration down to a value lower than the MPC was 0.25 g/L for Fe3O4 and 0.5 g/L for Co- and Ni-ferrites. Studying the desorption process, Hai et al. (2008) showed that 90% of the arsenic ions was desorbed from nanoparticles. After desorption, the nanoparticles did not show any difference in arsenic readsorption ability. Repeating the adsorption
desorption process four times, Hai et al. (2008) proved that the nanoparticles could be reused for arsenic removal.

7.4.4.2 Herpes DNA separation Herpes simplex virus, or herpes, causes extremely painful infections in humans (Ryan and Ray, 2004). Thus, the determination of the presence of herpes is important. A simple and fast way to recognize the presence of the DNA of the virus is to use an electrochemical sensor. However, electrochemical sensors exhibit a sensitivity limit, so they cannot measure concentrations lower than a few tens of nM/L (Tuan et al., 2005). Therefore, a virus DNA separation before the measurement by using the electrochemical sensor is needed in order to increase the concentration of the DNA. Hai et al. (2008) used a DNA sequence, which is representative of the herpes, as a probe to hybridize with the target DNA in the sample. After being activated with EDC and 1-methylimidazole (MIA), the probe DNA was mixed with the amino-NP to have nanoparticles with the probe DNA on the surface (DNA-NP). The herpes DNA separation was carried out as follows: 1 mL of the solution containing 2 wt.% of DNA-NP was mixed with 2
20 mL of a solution with 0.1 nM/L of the herpes DNA. The hybridization of the probe DNA and the target DNA appeared at 37 C for 1 hour. Then, the

7.4 Applications

nanoparticles with hybridized DNA were collected and redispersed in 0.1 mL of water using magnetic decantation. The dehybridization of the nanoparticles with the probe and target DNA was obtained at 98 C. Hai et al. (2008) obtained a solution with a high concentration of the DNA of the herpes virus after removing the DNA-NP from the solution by using magnetic decantation. When all the target DNA were separated, the DNA concentration had increased from 20 to 200 times. Fig. 7.4 shows the dependence of the output signal on the initial volume of the solution containing 0.1 nM/L of the herpes DNA before and after the magnetic separation (Hai et al., 2008). The initial solution contained 0.1 nM/L of the DNA, which was much smaller than the sensor sensitivity. Therefore, the output signals before magnetic enrichment were almost zero (Fig. 7.4, open squares). After magnetic enrichment, the output signals linearly increased with increasing initial solution volume, depending on the initial volume of the solution. The higher the volume, the higher the concentration. The result is higher output signals were obtained. This means that the concentration of the herpes DNA was much higher after the enrichment. With the highest initial volume that Hai et al. (2008) used in their studies, the concentration after magnetic enrichment was 200 times higher than the initial concentration.

10

V (mV)

8

6 After magnetic separation

4

2 Before magnetic separation 0 0

5 10 15 Initial volume (mL), concentration 0.,1 nM/L

20

FIGURE 7.4 Dependence of the output signal on the initial volume of solution containing herpes DNA before and after magnetic separation. After Hai, N.H., Chau, N., Luong, N.H., Anh, N.T.V., Nghia, P.T., 2008. Application of magnetite nanoparticles for water treatment and for DNA and cell separation. J. Korean Phys. Soc. 53, 1601
1606.

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7.4.4.3 CD41 cell separation In human immunodeficiency disease, such as HIV/AIDS, helper T cells (CD41 T cells) are considerably destroyed by HIV. For mechanisms of CD41 T cell depletion in HIV infection we refer the reader to the review of, for instance, Okoye and Picker (2013). A dropping number of CD41 T cells (which are often referred to as CD4 cells) in blood is an indicator of immunodeficiency as in the case of HIV/AIDS. The number of CD41 T cells in the blood of HIV-infected patients is often reduced to less than 500 cells/μL. According to the World Health Organization (WHO) classification, a person is diagnosed with AIDS if the CD4 count is less than 200 cells/μL (World Health Organization, 2007). Thus, the CD4 count is very important for doctors to adjust treatment strategies. The principle of counting the number of CD41 T cells in blood is based on the specific linker between the antiCD4 monoclonal antibody and CD41 T receptor on the lympho T surface (Casset et al., 2003; and references therein). Fluorescent-labeled antiCD4 antibody has been commonly used to count CD41 T cells of HIV/AIDS patients due to its binding specificity to the cells and fluorescent emission signals. However, the fluorescent signals of labeled CD41 T cells are sometimes interfered with by autofluorescence of other dead white cells, such as killers (CD81) T cells, B cells, macrophages, or neutrophils, which contribute to the background in detection. To minimize this background interference, CD41 T cells can be magnetically sorted from other cells in the blood, followed by fluorescent signal detection. Hai et al. (2008) and Khuat et al. (2008) used Fe3O4 MNPs coated with fluorescent-labeled antiCD4 antibody (antiCD4-MNPs) to count the CD41 T cells. The antiCD4-MNPs were prepared through covalent linking between the carboxyl group of the antiCD4 antibody and the amino group of amino-modified MNPs. The antiCD4-MNPs were then used as a material to conjugate with CD41 T cells for magnetic separation. These authors observed a number of cells bound with magnetic clusters and particles. Fig. 7.5 shows the conventional microscope visualization of the blood cells after being coupled with the antiCD4 antibody and antiCD4-MNPs and separated using a magnet (Hai et al., 2008). For observing the CD41 T cells, using fluorescence isothiocyanate labeled antiCD4-MNPs, the fluorescent intensity was improved by about two times compared to when cells were only labeled with the antiCD4 antibody. This result indicates the role of the MNPs and can be used for the treatment of an HIV-infected patient with a simple fluorescent microscope.

7.4.4.4 Detection of pathogenic viruses Purification of nucleic acids (DNA and RNA) from clinical samples is an important step in diagnostics, such as detection of pathogenic viruses and bacteria using the polymerase chain reaction (PCR), paternity testing, genetic research, DNA fingerprinting, and DNA sequencing. The nucleic acid purification method based on interaction with silica, developed by Boom et al. (1990), is commonly used. It

7.4 Applications

FIGURE 7.5 Microscope visualization of the blood cells under white light (A, C) and under blue light excitation (B, D), after being coupled with the antiCD4 antibody and antiCD4-MNPs and separated by using a magnet. After Hai, N.H., Chau, N., Luong, N.H., Anh, N.T.V., Nghia, P.T., 2008. Application of magnetite nanoparticles for water treatment and for DNA and cell separation. J. Korean Phys. Soc. 53, 1601
1606.

is known that DNA binds to silica, even though both DNA and the silica surface are negatively charged. Thus, to provide insight into important issues such as the mechanism behind DNA binding to silica is of great interest. Using molecular dynamics simulations, Shi et al. (2015) showed that the two major mechanisms for binding of DNA to silica are attractive interactions between DNA phosphate and surface silanol groups and hydrophobic bonding between DNA base and hydrophobic region of silica surface. These short-range attractions can be sufficiently strong to overcome the electrostatic repulsion between negatively charged DNA and negatively charged silica surface.

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Micrometer-size silica-coated magnetic beads have been developed by different groups (see, for instance, Akutsu et al., 2004) and biotech companies such as Roche Diagnostics, Life Technologies, Promega, and Beckman Coulter to improve the efficiency of purification. Berensmeier (2006) described methods based on magnetic microparticles for nucleic acid purification. Recently, the investigation and application of silica-coated MNPs for separation and purification of nucleic acids has become an emerging area. Ashtari et al. (2005) reported a method for recovery of target ssDNA using amino-modified silica-coated MNPs and used them to recover trace concentrations of target ssDNA fragments of severe acute respiratory syndrome virus with high efficiency and good selectivity. Quy et al. (2013) presented a method for synthesis of the silica-coated Fe3O4 MNPs and their application for isolation and enrichment of DNA of Epstein
Barr virus (EBV), which is associated with particular cancers and lymphoma, and hepatitis virus type B (HBV) which causes hepatitis. Quy et al. (2013) have shown that the purification efficiency of DNA of both EBV and HBV using synthesized silica-coated Fe3O4 MNPs was superior to that obtained with commercialized silica-coated Fe3O4 magnetic microparticles. Quy et al. (2013) reported also on time saving in detection of EBV and HBV, namely the time required for DNA purification using silica-coated Fe3O4 nanoparticles was significantly reduced as the particles were attracted to magnets more quickly (15
20 seconds) than the commercialized silica-coated Fe3O4 microparticles (about 2
3 minutes). These results were attributed to the fact that silica-coated Fe3O4 nanoparticles have a larger total surface area compared to that of the commercialized silica-coated Fe3O4 microparticles.

7.4.4.5 Specific and rapid tuberculosis detection The worldwide effort to eradicate tuberculosis (TB), the highly infectious disease caused by Mycobacterium tuberculosis (MTB), has thus far led to significant decreases in the number of incidents and mortality rates. TB, however, remains the second leading cause of death from an infectious disease and a major global health problem (World Health Organization, 2011). Unfortunately, in the absence of an effective screening method, there are many cases of TB and multidrugresistant-TB which are not opportunely detected or treated. In the early 1990s, a diagnostic procedure based on the amplification of the insert sequence (IS) 6110 was developed and soon became prevalent. This method is displaying advantages regarding detection limit and specificity through the amplification of this signature sequence using the PCR technique (Kolk et al., 1992, 1998; Kox et al., 1994; Sankar et al., 2011; Shukla et al., 2011). However, this procedure requires the time-consuming extraction of DNA from each sample, including a cell lysis step which is usually inefficient on account of the highly complex bacterial cell wall (Noordhoek et al., 1994; Ellis and Zabrowarny, 1993; Ogbaini-Emovon, 2009). Recently, the collaboration between biologists and physicists has allowed the development of nanomaterials in DNA extraction from different organisms. More importantly, using MNPs, multiple samples could be processed simultaneously on

7.4 Applications

a microtiter plate, which would enhance the testing rate and reduce the contamination risk for testing personnel, especially in the case of dangerous pathogens (e.g., TB). Furthermore, this material could be constructed to form bioconjugates containing specific antibodies which would enhance the specificity of the detection method (Arruebo et al., 2009). Recently, Pham et al. (2015) reported for the first time the development of a specific and rapid TB detection using MNPs. The MNPs were functionalized with amino groups to facilitate coupling with anti-TB antibodies. The coupled nanoparticles were used to enrich Mycobacterium. In addition, preliminary assessment of this method in testing clinical samples (sputum and throat wash specimens) was also noted. The results of this study indicated potential for the establishment of a high-throughput semiautomated TB diagnostic procedure, which is currently being studied. Specificity, or the capability of improving signal-to-noise ratio, is a critical criterion in any diagnostic procedure. Samples collected from patients (sputum in most cases) normally contain other microorganisms which might be the contamination source. By pretreatment with N-acetyl L-cysteine-sodium hydroxide (NALC-NaOH), the decontamination could be done for sputum samples. This technique, however, could not eliminate nonspecific signal entirely. Besides the specifically designed primers for the amplification of the signature sequence IS6110, the coupled anti-MTB antibody served as a sieve which captured only the MTB antigens. The whole procedure was done in approximately one hour, which was half of the total time required for the traditional DNA extraction method.

7.4.4.6 Biological treatment targeting Mycobacterium tuberculosis in contaminated wastewater Wastewater from hospitals and facilities receiving patients infected with contagious microorganisms has dense concentrations of these pathogens, which may represent a danger to public health. Therefore, proper wastewater treatment to remove these contaminants before discharging to the sewage system is a great societal concern. Most common wastewater treatment methods are divided into physical (heating, ultraviolet radiation, etc.), chemical (e.g., hypochlorite/chlorination, ozonation), and biological categories. The main disadvantages of the first two categories are complex implementation and high maintenance cost (e.g., due to corrosion of the pipe systems). With the additional advantage of being environmentally friendly, biological methods have become valuable alternatives. Most of these methods utilize live microorganisms in either fermentation processes to remove toxic chemicals or filtration applications through the formation of biofilm (Sewage water treatment vat., 2016) and, thus, are without specific targets. Nguyen et al. (2016) reported biological treatment targeting MTB in contaminated wastewater using lysing enzymes coupled to Fe3O4 MNPs. This study was a further development from previous results obtained with a complex comprised of magnetic amino nanoparticles and anti-TB antibody molecules (Pham et al., 2015). The complex, referred to as NP-NH2-anti-TB, was shown to be capable of specifically capturing MTB (Pham et al., 2015), which would be killed with the

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addition of lysing enzymes. The major role of the nanoparticles is to bring these molecules in close proximity so that the lysing enzymes can work on the bacteria captured through the conjugated antibody on the same surface area. This, ideally, would solve the limit of diffusion, thus enhancing the reaction rate. Nguyen et al. (2016) also reported an initial assessment of the developed method in a wastewater model by spiking the wastewater samples collected from a hospital and a facility receiving TB patients with Mycobacterium bovis from bacillus CalmetteGue´rin vaccine. The results of this study indicated potential applications of the NP-NH2-anti-TB complex combined with enzymes to efficiently treat MTB-contaminated wastewater.

7.4.5 APPLICATIONS OF MULTIFUNCTIONAL NANOPARTICLES Multifunctional nanoparticles are gradually attracting more and more attention because of their ability to combine numerous properties, such as electronic, magnetic, optical, and catalytic. They are highly functional materials with modified properties which can be quite different from those of the individual materials. The properties of core
shell nanoparticles can be modified by changing either the constituting materials or the core-to-shell ratio (Oldenburg et al., 1998). Multifunctional nanoparticles show distinctive properties of the different materials employed together to meet the diverse application requirements. The purpose of the functionalization is manyfold, such as surface modification, the ability to increase the functionality, dispersibility, and stability, controlled release of the single nanoparticles, reduction in consumption of materials, etc. Applications of different multifunctional nanoparticles are summarized in review articles by Karele et al. (2006), Seleci et al. (2016), Jia et al. (2013), and Bao et al. (2013). The multifunctional nanoparticles are widely used in various applications such as pharmaceutical applications (Caruso, 2001), biomedical (Balakrishnan et al., 2009; Salgueirino-Maceira and Correa-Duarte, 2007), catalysis (Daniel and Astruc, 2004; Phadtare et al., 2003), electronics (Kortan et al., 1990; Qi et al., 1996), enhancing photoluminescence (Mews et al., 1994; Kamat and Shanghavi, 1997), creating photonic crystals (Scodeller et al., 2008), etc. Especially in the biomedical field, these nanoparticles are used for bioimaging (Laurent et al., 2008; Babes et al., 1999; Dresco et al., 1999), controlled drug release (Dresco et al., 1999), targeted drug delivery (Laurent et al., 2008; Gupta and Gupta, 2005; Dresco et al., 1999; Yan et al., 2009), cell labeling (Laurent et al., 2008; Jaiswal et al., 2003; Michalet et al., 2005), and tissue engineering applications (De et al., 2008). For instance, core
shell nanoparticles have attracted considerable attention in clinical and therapeutic applications (Hirsch et al., 2003; Loo et al., 2004). Core
shell nanoparticles, which are strong absorbers, can be used in photothermal therapy, while those which are efficient scatterers can be used in imaging applications. Silica core
gold shell nanoshells, a novel core
shell nanostructure, which either absorb or scatter light effectively, can be designed by varying their core-to-shell ratio (Loo et al., 2004). In imaging applications of core
shell

7.4 Applications

nanoparticles, they can be conjugated with specific antibodies for diseased tissues or tumors. When conjugated nanoparticles are inserted in the body, they get attached to diseased cells and can be imaged. In parallel, when the tumor has been located, resonance wavelength absorption of the core
shell nanoparticles will lead to localized heating of the tumor and it is destroyed. In other words, the imaging and photothermal therapy can be carried out together with core
shell or multifunctional nanoparticles. In drug-delivery systems using core
shell nanoparticles, the drug can be encapsulated or adsorbed onto the nanoparticle surface (Sparnacci et al., 2002) via a specific functional group or by an electrostatic stabilization technique. The nanoparticles will come into contact with the biological medium, and then direct the drug. For instance, the enzyme- and antibodyconjugated core
shell nanoparticles, which are strong absorbers with gold shells, can be embedded in a matrix of the polymer, such as nisopropylacrylamide (NIPAAm), and acrylamide (AAm) (West and Halas, 2000). These polymers exhibit a melting temperature which is slightly above body temperature. If the core
shell nanoparticles absorb heat from the illumination with resonant wavelength, the heat will transfer to the local environment, then cause collapse of the polymer matrix and release of the drug. Furthermore, when the core is MNPs, the core
shell nanoparticles with the bifunction of magnetic and gold nanoparticles can drive the drug and kill the tumor under the external magnetic field as well as by the irradiation of resonance wavelength. The usual methods of tumor treatment, such as chemotherapy or radiotherapy, have various side effects such as substantial loss of hair, lack of appetite, diarrhea, etc. The process of attacking the tumor also leads to the loss of many healthy cells. Core
shell or multifunctional nanoparticles offer an effective and relatively safer strategy to cure these ailments by significantly reducing the amount of chemicals or radiation using local treatments. Another strategy of using multifunctional nanoparticles is using multiple types of nanoparticles in one application, such as in fast DNA diagnosis (Quynh et al., 2014). This fast DNA kit created from NH2-modified SiO2-coated Fe3O4 nanoparticles and highly fluorescent Mn-doped ZnS nanoparticles in a sandwich structure, which can be seen in Fig. 7.6. The sandwich configuration attached the fluorescent particles to the docking matrix of MNPs with the complementary hybridization of the detector probe
target
capture probe structure. In one side of this sandwich structure, SiO2-coated Fe3O4 nanoparticles, which were modifed by the NH2 group, were employed as a docking matrix. The docking matrix was linked with a capture probe oligonucleotide chain, which specifically identifies the target DNA. In the other side of the sandwich, the detector probe formed by the signaling semiconductor nanoparticles contacted with another oligonucleotide chain. This sandwich configuration was applied to detect DNA of EBV using separation function of MNPs and the signaling function of semmiconductor nanoparticles. The kit firstly was stored as three separated solutions containing magnetic probe nanoparticles, semiconductor detector nanoparticles, and target DNA molecules, respectively. In order to measure the target DNA concentration, those solutions

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FIGURE 7.6 Schematic sandwich structure of DNA detection Fast kit using multifunctional magnetic
semiconductor nanoparticles. After Quynh, L.M., Hieu, N.M., Nam, N.H., 2014. Fast DNA diagnostic using Fe3O4 magnetic nanoparticles and light emitting ZnS/Mn nanoparticles, VNU J. Sci.: Math.
Phys. 30(3), 1
11.

were mixed to assemble the magnetic donor
target DNA
semiconductor detector complexes via the specific hybridization of catcher probe and detector probe with the target DNA. The complexes, then, are easily collected by an outside magnetic field. The other components, which do not contain MNPs will be washed out. The collected complexes were redistributed in solution and measured by photoluminescence. The luminescent intensity at 586 nm of Mn-doped ZnS nanoparticles changes with changing the initially added DNA target concentration. The detection limit of target DNA is around 2 3 106 copies/mL (B0.3 fM), showing the ability of using the named multifunctional magnetic
semiconductor sandwich structure for fast KIT DNA detection during scene investigation and viral DNA detection. Finally, in addition to the improved material properties, multifunctional materials are also important from an economic point of view. Multifunctional nanoparticle-based drug-delivery systems have been developed to improve the efficiency and reduce the systemic toxicity of a wide range of drugs, where additional capabilities like targeting and image contrast enhancement added to the nanoparticles. However, additional functionality means additional synthetic steps and costs, more convoluted behavior and effects in vivo, and also greater regulatory hurdles. The tradeoff between additional functionality and complexity is discussed by Cheng et al. (2012).

7.5 CONCLUSION AND PERSPECTIVES This chapter reviews various methods of synthesis and functionalization of metallic, semiconductor, magnetic, and multifunctional nanoparticles. Some applications of the fabricated nanoparticles in life sciences and the environment are discussed.

References

In the synthesis domain, it is expected that new preparation approaches will be introduced allowing the use of less energy and less toxic materials (“green manufacturing”). In order to meet requirements for different applications, the functionality of nanoparticles becomes more complex. Thus the major trend in the further development of nanoparticles is to make them multifunctional, with the potential to integrate various functionalities. Smart multifunctional nanoparticles will be very promising for a variety of applications.

ACKNOWLEDGMENT The authors would like to thank Prof. N.H. Hai, Prof. N.T.V. Anh, Prof. P.T. Nghia, Dr. P. Yen, Mr. L.M. Quynh, Dr. I. Notingher, and Prof. M. Henini for close collaboration.

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